Age-dependent osteoprotective effects of hydroxytyrosol acetate: enhanced bone integrity via gut–bone axis activation

Osteoporosis, a disorder with reduced bone mass and biomechanical properties, poses a geriatric health challenge. Though natural antioxidants like hydroxytyrosol acetate (HT-ac) have diverse regulatory effects, its impact on bone health is underexplored. This study examined HT-ac's age-specific effects on bone health in murine models. Mice were allocated to control and HT-ac groups, with the latter receiving HT-ac for 20 weeks. Assessments included bone density, microarchitecture, and biomechanical evaluation, alongside gut microbiota analysis and detection of reactive oxygen species (ROS). Results showed HT-ac increased bone mineral content and improved trabecular properties in both age groups. However, young mice exhibited adverse effects including fat accumulation, inflammation, and elevated ROS levels, while such effects were absent in aged mice. Gut microbiota – metabolomic integration revealed HT-ac's osteoprotective effects correlated with gut microbiota changes and l-carnitine upregulation. Taken together, long-term HT-ac offers age-independent osteoprotection via gut microbiota-dependent l-carnitine biosynthesis. The differing outcomes highlight the need for age-specific strategies in osteoporosis intervention.